The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art to the presently claimed invention, nor that any of the publications specifically or implicitly referenced are prior art to that invention.
Exendin The exendins are peptides that are found in the venom of the Gila-monster, a lizard common in Arizona and Northern Mexico. Exendin-3 [SEQ. ID. NO. 1] is present in the venom of Heloderma and exendin-4 [SEQ. ID. NO. 2] is present in the venom of Heloderma suspectum (Eng, J., et al., J. Biol. Chem., 265:20259-62, 1990; Eng., J., et al., Chem., 267:7402-05, 1992). The amino acid sequence of exendin-3 is shown in FIG. 2. The amino acid sequence of exendin-4 is shown in FIG. 3. The exendins have some sequence similarity to several members of the glucagon-like peptide family, with the highest homology, 53%, being to [SEQ. ID. NO. 3] (Goke, et al., J. Biol. Chem., 268:19650-55, 1993). also known as proglucagon[78-107] or simply, “GLP-1,” has an insulinotropic effect, stimulating insulin secretion from pancreatic The amino acid sequence of GLP-1 is shown in FIG. 4. GLP-1 also inhibits glucagon secretion from pancreatic et al., Diabetes, 42:658-61, 1993; D'Alessio, et al., J. Clin. Invest., 97:133-38, 1996). GLP-1 is reported to inhibit gastric emptying (Willms B, et al., J Clin Metab 81 (1): 327-32, 1996; Wettergren A, et al., Dig Dis Sci 38 (4): 665-73, 1993), and gastric acid secretion. Schjoldager et al., 34 (5): 7-03-8, 1989; O'Halloran D J, et al., J 126 (1): 665-73, 1993). GLP-1[7-37], which has an additional glycine residue at its carboxy terminus, also stimulates insulin secretion in humans et al., Diabetes, 42:658-61, 1993). A transmembrane G-protein adenylate-cyclase-coupled receptor believed to be responsible for the insulinotropic effect of GLP-1 has been cloned from a line (Thorens, Proc. Natl. Acad. Sci. USA 89:8641-45 (1992)).
Exendin-4 reportedly acts at GLP-1 receptors on insulin-secreting cells, at dispersed acinar cells from guinea pig pancreas, and at parietal cells from stomach; the peptide is also said to stimulate somatostatin release and inhibit gastrin release in isolated stomachs (Goke, et al., Them. 268:19650-55, 1993; Schepp, et al., Eur. J. Pharmacol., 1994). Exendin-3 and exendin-4 were reportedly found to stimulate cAMP production in, and amylase release from, pancreatic acinar cells (Malhotra, R., et al., Regulators 1992; Raufman, et al., 267:21432-37, 1992; Singh, et al., 53:47-59, 1994). Based on their insulinotropic activities, the use of exendin-3 and exendin-4 for the treatment of diabetes mellitus and the prevention of hyperglycemia has been proposed (Eng, U.S. Pat. No. 5,424,286).
Agents which serve to delay gastric emptying have found a place in medicine as diagnostic aids in gastro-intestinal radiologic examinations. For example, glucagon is a polypeptide hormone which is produced by the a cells of the pancreatic islets of Langerhans. It is a hyperglycemic agent which mobilizes glucose by activating hepatic glycogenolysis.
It can to a lesser extent stimulate the secretion of pancreatic insulin. Glucagon is used in the treatment of insulin-induced hypoglycemia, for example, when administration of glucose intravenously is not possible.
However, as glucagon reduces the motility of the gastro-intestinal tract it is also used as a diagnostic aid in gastro-intestinal radiological examinations. Glucagon has also been used in several studies to treat various painful gastro-intestinal disorders associated with spasm. Daniel, et al. Med. J., 3:720, 1974) reported quicker symptomatic relief of acute diverticulitis in patients treated with glucagon compared with those who had been treated with analgesics or antispasmodics. A review by Glauser, et al., (J. Am. Coll. Emergency Physns, 8:228, 1979) described relief of acute esophageal food obstruction following glucagon therapy. In another study glucagon significantly relieved pain and tenderness in 21 patients with biliary tract disease compared with 22 patients treated with placebo (M. J. Stower, et al., J. Surg., 69:591-2, 1982).
Methods for regulating gastrointestinal motility using amylin agonists are described in International Application No. PCT/US94/10225, published Mar. 16, 1995.
Methods for regulating gastrointestinal motility using exendin agonists are described in a U.S. patent application Ser. No. 08/908,867.
Certain exendin agonists are described in U.S. Provisional Application No. 60/065,442 filed Nov. 14, 1997 and in U.S. Provisional Application Ser. No. 60/066,029 filed Nov. 14, 1997.
According to one aspect, the present invention provides novel exendin agonist compounds which exhibit advantageous properties which include effects in slowing gastric emptying and lowering plasma glucose levels.
According to the present invention, provided are compounds of the formula (I) [SEQ. ID. NO. 4]: 1 5 10 Gly Thr 15 20 Ser Lys Gln Glu Glu Glu Ala Val Arg Leu 25 30 Xaa12 Leu Lys Asn Gly Gly Xaa14 35 Ser Ser Gly Ala Xaa15 Xaa16 Xaa17 Xaa18-Z wherein is His, Arg or Tyr; is Ser, Gly, Ala or Thr; is Asp or Glu; is Phe, Tyr or naphthylalanine; Xaa5 is Thr or Ser; is Ser or Thr; is Asp or Glu; is Leu, Ile, Val, pentylglycine or Met; is Leu, Ile, pentylglycine, Val or Met; Xaa10 is Phe, Tyr or naphthylalanine; is Ile, Val, Leu, pentylglycine, tert-butylglycine or Met; is Glu or Asp; Xaa13 is Trp, Phe, Tyr, or naphthylalanine; Xaa14, Xaa15, and Xaa17 are independently Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine or N-alkylalanine; is Ser, Thr or Tyr; and Z is —OH or —NH2; with the proviso that the compound does not have the formula of either SEQ. ID. NOS. 1 or 2. Also included within the scope of the present invention are pharmaceutically acceptable salts of the compounds of formula (I) and pharmaceutical compositions including said compounds and salts thereof.
Also provided are compounds of the formula [SEQ. ID. NO. 36]: 1 5 10 Gly Thr Xaa5 15 20 Ser Lys Gln Glu Glu Glu Ala Val Arg Leu 25 30 Xaa10 Xaa11 Xaa12 Xaa13 Leu Gly Gly Xaa14 35 Ser Ser Gly Ala Xaa15 Xaa16 Xaa17 Xaa18-Z wherein is His, Arg, Tyr or 4-imidazopropionyl; is Ser, Gly, Ala or Thr; is Asp or Glu; is Phe, Tyr or naphthylalanine; Xaa5 is Thr or Ser; is Ser or Thr; is Asp or Glu; is Leu, Ile, Val, pentylglycine or Met; is Leu, Ile, pentylglycine, Val or Met; Xaa10 is Phe, Tyr or naphthylalanine; Xaa11 is Ile, Val, Leu, pentylglycine, tert-butylglycine or Met; Xaa12 is Glu or Asp; Xaa13 is Trp, Phe, Tyr, or naphthylalanine; X1 is Lys Asn, Asn Lys, R Asn, Asn where R is Lys, Arg, straight chain or branched alkanoyl or cycloalkylalkanoyl; Xaa14, Xaa16 and are independently Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine or N-alkylalanine; Xaa18 is Ser, Thr or Tyr; and Z is —OH or —NH2; with the proviso that the compound does not have the formula of either SEQ. ID. NOS. 1 or 2. Also included within the scope of the present invention are pharmaceutically acceptable slats of the compounds of formula and pharmaceutical compositions including said compounds and salts thereof.
Definitions In accordance with the present invention and as used herein, the following terms are defined to have the following meanings, unless explicitly stated otherwise.
The term “amino acid” refers to natural amino acids, unnatural amino acids, and amino acid analogs, all in their D and L stereoisomers if their structure allow such stereoisomeric forms. Natural amino acids include alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine (Cys), glutamine glutamic acid (Glu), glycine histidine isoleucine (Ile), leucine Lysine (Lys), methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), typtophan (Trp), tyrosine (Tyr) and valine Unnatural amino acids include, but are not limited to azetidinecarboxylic acid, 2-aminoadipic acid, 3-aminoadipic acid, beta-alanine, aminopropionic acid, 2-aminobutyric acid, 4-aminobutyric acid, 6-aminocaproic acid, 2-aminoheptanoic acid, 2-aminoisobutyric acid, 3-aminoisbutyric acid, 2-aminopimelic acid, tertiary-butylglycine, 2,4-diaminoisobutyric acid, desmosine, acid, 2,3-diaminopropionic acid, N-ethylglycine, N-ethylasparagine, homoproline, hydroxylysine, allo-hydroxylysine, 3-hydroxyproline, 4-hydroxyproline, isodesmosine, allo-isoleucine, N-methylalanine, N-methylglycine, N-methylisoleucine, N-methylpentylglycine, N-methylvaline, naphthalanine, norvaline, norleucine, ornithine, pentylglycine, pipecolic acid and thioproline. Amino acid analogs include the natural and unnatural amino acids which are chemically blocked, reversibly or irreversibly, or modified on their N-terminal amino group or their side-chain groups, as for example, methionine sulfoxide, methionine sulfone, S-(carboxymethyl)-cysteine, S-(carboxymethyl)-cysteine sulfoxide and S-(carboxymethyl)-cysteine sulfone.
The term “amino acid analog” refers to an amino acid wherein either the C-terminal carboxy group, the N-terminal amino group or side-chain functional group has been chemically codified to another functional group. For example, aspartic acid-(beta-methyl ester) is an amino acid analog of aspartic acid; N-ethylglycine is an amino acid analog of glycine; or alanine carboxamide is an amino acid analog of alanine.
The term “amino acid residue” refers to radicals having the structure: (1) —C(O)—R—NH—, wherein R typically is —CH(R′)—, wherein R′ is an amino acid side chain, typically H or a carbon containing substitutent; or (2), wherein p is 1, 2 or 3 representing the azetidinecarboxylic acid, proline or pipecolic acid residues, respectively.
The term “lower” referred to herein in connection with organic radicals such as alkyl groups defines such groups with up to and including about 6, preferably up to and including 4 and advantageously one or two carbon atoms. Such groups may be straight chain or branched chain.
“Pharmaceutically acceptable salt” includes salts of the compounds of the present invention derived from the combination of such compounds and an organic or inorganic acid. In practice the use of the salt form amounts to use of the base form. The compounds of the present invention are useful in both free base and salt form, with both forms being considered as being within the scope of the present invention.
In addition, the following abbreviations stand for the following: “ACN” or “CH3CN” refers to acetonitrile. or “Tboc” refers to t-butoxy carbonyl.
“DCC” refers to N,N′-dicyclohexylcarbodiimide.
“Fmoc” refers to fluorenylmethoxycarbonyl.
refers to 2-(1H-benzotriazol-1-yl)-hexaflurophosphate.
refers to 1-hydroxybenzotriazole monohydrate.
or refers to homoproline.
“MeAla” or “Nme” refers to N-methylalanine.
“naph” refers to naphthylalanine.
“pG” or pGly” refers to pentylglycine.
refers to tertiary-butylglycine.
“ThioP” or tPro” refers to thioproline.